11:10-12:00, Rm 103

Cancer biologyB-17-01TrkC plays an essential role in breast tumor growth and metastasis bysuppression of apoptosisWook Jin, Gyoung Mi Kim, Min Soo KimLaboratory of Molecular disease and cell regulation, Lee Gil Ya Cancer and Diabetes Institute,Gachon University of Medicine and Science, Incheon 406-840, KoreaFor most cancer cell types, the acquisition of metastatic ability leads to clinically incurabledisease. Despite the obvious importance of metastasis, the process remains incompletelycharacterized at the molecular and biochemical levels. However, one invariable feature ofthe metastatic process is deregulated gene expression, which affects sequential stagesof tumor cell invasion, organ tropism, and growth at distant sites. In a search for keyregulators of metastasis, we have found that the TrkC plays an essential role inmetastasis. Here, we report that TrkC is frequently overexpressed in human breastcancers and plays an essential role in tumor growth and metastasis. Ectopic expressionof TrkC in non-malignant mammary epithelial cells suppressed anoikis, which correlatedwith activation of the Ras-mitogenactivated protein kinase and phosphatidylinositol-3-OHkinase (PI3K)/Akt pathways, and reduced expression of the metastatic regulator Twist.Furthermore, suppression of TrkC expression in highly metastatic mammary carcinomacells inhibited their growth in vitro, as well as their ability to metastasize from themammary gland to the lung in vivo. These results have identified TrkC as a criticalregulator of breast cancer cell growth and metastasis.B-17-04TrkB is a key regulator of the EMT program in breast cancerWook Jin, Min Soo Kim, Gyoung Mi KimLaboratory of Molecular disease and cell regulation, Lee Gil Ya Cancer and Diabetes Institute,Gachon University of Medicine and Science, Incheon 406-840, KoreaMetastasis is a multistep process during which cancer spreads from the place at which itfirst arose as a primary tumor to distant locations in the body. TrkB, a member of the Trkfamily of neurotrophin receptors, is implicated in the growth and survival of humancancers. Here we report that results in the TrkB plays an essential role in tumor growthand metastasis and is frequently overexpressed in human breast primary tumor andhighly metastatic human breast cancer cell lines. Furthermore, we show that suppressionof TrkB in highly metastatic mammary carcinoma cells specifically induces anoikis, andsuppress cell growth, formation of soft agar colonies, and nuclear translocation of STAT3,which correlated with activation of Ras-MAPK and the phosphatidylinositol-3-OHkinase/Akt pathway. Moreover, Ectopic expression of TrkB results in loss of E-cadherin,activation of N-cadherin, induction of Twist-1 and Twist-2, contributes to metastasis bypromoting an epithelial-mesenchymal transition (EMT). Also, TrkB is associated with c-Src and Jak2 and this complex formation regulates activity of STAT3 and Twist-1 andTwsit-2 as its downstream target. These findings establish a direct link between TrkBsuch as upstream activator of Twist-1 and Twist-2, EMT, and tumor metastasis.B-17-02TrkB suppresses TGFβsignaling by suppression of Smad4 translocationWook Jin, Gyoung Mi Kim, Min Soo KimLaboratory of Molecular disease and cell regulation, Lee Gil Ya Cancer and Diabetes Institute,Gachon University of Medicine and Science, Incheon 406-840, KoreaTrkB, a member of the Trk family of neurotrophin receptors, is a potent oncoproteinexpressed in tumor derived form multiple cell lineasges, functions as a constitutivelyactive protein tyrosine kinase and implicated in the growth and survival of humancancers. Here, we show that TrkB suppresses TGF beta signaling by directly binding tothe Smad2/Smad3/Smad4, thereby preventing it by TGF beta induced Smad4 nucleartranslocation. This activity requires a functional TrkB protein tyrosine kinase, and Smad2,smad3, and Smad4 appears to be a direct target of TrkB. Furthermore, we show thatsuppression of TrkB in highly metastatic mammary carcinoma cells specifically inducesanoikis, and suppress cell growth, formation of soft agar colonies. Our findings provideevidence for a previously undescribed mechanism by which oncogenic tyrosine kinasescan block TGF beta tumor suppressor activity.B-17-05Cancer up-regulated gene(CUG)2-mediated activation of Stat1 confersresistance to oncolytic vesicular stomatitis virus infectionWaraporn Malilas, Srisuttee Ratakorn, Boonying Wassamon, Sang Seok Koh¹andYoung-Hwa ChungDepartment of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 and¹Therapeutic Antibody Resaerch Center, Korea Research Insitute of Bioscience and Biotechnology,Daejeon 305-333, KoreaWe have recently found a novel oncogene, the cancer up-regulated gene(CUG)2, thatwas elevated in a variety of tumor tissues such as ovary, liver, lung and pancreas. Furtherstudies have also shown that CUG2 expression enhances Ras activity andphosphorylation of MAPKs such as ERK, JNK and p38 MAPK. We thus examinedwhether vesicular stomatitis virus(VSV) could efficiently induce cytolysis in cancer cellsexpressing CUG2 and thus be used as a potential cancer therapeutic agent. Here, wefound that NIH3T3 cells stably expressing CUG2(NIH-CUG2) are resistant to VSVinfection while NIH3T3 cells stably expressing a vector(NIH-Vec) are susceptible to VSVinfection and virus-induced apoptosis. The resistance of NIH-CUG2 cells to VSV may beexplained by activation of Stat1 and increase of ISRE-mediated transcription, leading totype I IFN production. Akt and JNK are involved in CUG2-mediated activation of Stat1whereas ERK and p38 MAPK are not. We are under investigation whether suppressionof Stat1 with its siRNA sensitizes VSV-mediated apoptosis. Taken together, we speculatethat Stat1 activation mediated by CUG2 provides resistance to VSV infection. [Supportedby grants from World Class University program through NRF(R31-2008-20004-0)]B-17-03TrkC Promotes Tumor Metastasis In Invasive Breast Cancer ThroughInducing Epithelial-Mesenchymal Transition By Activation Of JAK2-STAT3-Twist AxisWook Jin, Gyoung Mi Kim, Min Soo KimLaboratory of Molecular disease and cell regulation, Lee Gil Ya Cancer and Diabetes Institute,Gachon University of Medicine and Science, Incheon 406-840, KoreaMetastasis is a multistep process during which cancer cells disseminate from the site ofprimary tumors and establish secondary tumors in distant organs. Here we show thatTrkC, a member of the Trk family of neurotrophin receptors, is frequently overexpressedin human breast cancers. Also, enforced expression of TrkC induces epithelialmesenchymaltransitions (EMTs) by upregulating Twist-1 and Twist-2. In addition, TrkCenhanced metastatic potential and induced proliferation. Moreover, TrkC is associatedwith c-Src-Jak2, and this complex induces Twist-1 and Twist-2 levels by regulating theactivity of STAT3. These findings suggest that TrkC plays a central role in promotinginvasion and metastasis, and that it may prove to be a highly specific molecular markerfor human basal-like breast cancers.B-17-06P53 mutation is refractory to the Growth inhibitory effects ofchlorophyll in cultured glioblastoma cellsSeungae Kim, Seungchan Kim, Wooseok Lim, Hyogun Lee¹Hana high school, Seoul, Korea, ²Department of Biotechnology, Yonsei University, Seoul, Korea,³Clinical Research Institute, Seoul National University Hospital, Seoul, KoreaActivation or mutation in oncogene is signal for the oncogenesis, and p53 is one thatmediate in glioblastoma. To test p53 mutation affects on chlorophyll. U87 glioblastomaand p53 mutated U251 cells were used as an experimental model. Chlorophyll a and bfrom spinach were incubated together at a concentration ranging from 1 nM to 100 nM.Growth was determined by cell counting using hemocytometer or WST-1 assay. Todetermine inhibitory mechanism, survival signals (Akt, ERK, pERK), apoptosis (pPTEN,Bax, caspase 3, p21) or cell cycle cdk1/cdc2 expression were assessed. Hoescht 33382nuclear staining was performed. Statistical analysis was done by box plotting and Studentt-test. From 1nM to 100 nM, there was dose-dependent growth inhibitory effect in U87 butnot in U251 cells. When compared to the U87 cells, ERK phosphrylation was increasedwhereas cdk1/cdc2 was decreased in U251 cells. Chromatin condensation or nuclearfragmentation was not detected. In conclusion, mutation of p53 in glioblastoma reducesthe growth inhibitory effect of chlorophyll by affecting ERK survival signal or cell cycleinvolving cdk1/cdc2 in cultured glioblastoma cells.168 Korean Society for Biochemistry and Molecular Biology